Today, Part IV is all about the explanations for the spectacular drop in measles case-fatality rates (between 40 and 150 times lower death rate per case of measles) in the first half of the 20th century (chart). No one of these explanations alone seems to be completely adequate to explain the spectacular decline in measles deaths, but perhaps — probably — the combination of all of them put together, perhaps with contributions from some of the Part III explanations, account for the drop.

Explanations that (might be) right:

Better treatment of measles, especially antibiotics. Measles is a viral disease and so not treatable by antibiotics, but it’s the secondary infections that kill; and those could be controlled by antibiotics.

Reduction in crowding. There’s evidence that overcrowding, per se, can make severe measles disease more common. Improved living conditions might have helped with this.

Demographic changes. This is a little vague, but I have a couple of specific aspects in mind.

Nutrition. This is the most popular, and probably most important, explanation. But (to me, anyway) it doesn’t seem to be enough, all by itself.

Vitamin A. As a subset of nutrition, and also as a treatment on its own.

Let’s leave nutrition to the last and quickly run through the other explanations first.

• First: Better medical treatment of measles patients. As I say, antibiotics probably put a big dent into the toll from secondary bacterial infections. There were also advances in things like oxygen treatment during pneumonia and so on. Probably important factors, but the problem with this explanation is that by the time antibiotics became available, the trend to reduced measles mortality was already well under way. You don’t see sudden drops in mortality associated with these things kicking in, just a continuation of the ongoing decline.

Compare to the chart of overall mortality rates in the 20th century1 (to the left; this is the inset from the larger chart here). It shows two curves being fit to the data — one in the first 30-odd years of the 20th century, one in the second half of the 20th century. From 1938 to 1953, between those smooth curves, there’s an especially dramatic drop in mortality rates. That abrupt drop corresponds to the introduction of antibiotics. You don’t see that abrupt drop with measles death rates.

• Reduction in crowding. This seems like a simple thing, but it’s been proposed (first, I believe, by Aaby and Coovadia,2 in 1985) to be a major influence on measles mortality.

Their observations suggested that severe measles cases are most closely associated, not with malnutrition as you might expect, but with overcrowding. (Obviously, the two are both tightly linked to poverty in general, so pulling them apart is a little tricky.) They argue that you’re more likely to get a large dose of measles virus if you’re crowded together with a measles patient, and that getting more virus at the outset correlates with having more severe disease:

It was found that severe measles was not associated with PEM [protein-energy-malnutrition] but frequently accompanied overcrowding in Guinea-Bissau. Secondary cases fared worse than index patients. … The hypothesis which fits most of the observed facts postulates that the transmission of a large inoculum of virus particles to susceptible children is an important cause of severe disease. 2

(My emphasis) So, as overall wealth improved in the early 20th century and quality of life became better, children became less crowded, less likely to receive massive doses of virus, and were better able to control the lower doses they did get.

This makes sense, but I don’t think there’s enough of an effect to account for the drop in mortality — again, we need to explain a hundred-fold reduction in the case-fatality rate. This is probably one significant factor, but not enough to account for everything.

• Reduction in crowding is a part of the next category, Demographic changes. This is much harder, for me anyway, to put together with hard data, but follow me here:

We know that measles mortality rates are by far the highest in the youngest of its victims. Children over, say, 5 years old or so are much less likely to die than are infants.3 So, any changes in society that would make measles more likely to infect older — even slightly older — children, would have a massive effect on mortality rates. We see this even today, where small changes in age at infection lead to significant changes in survival. 4

Meanwhile, we see measles mortality rates beginning to drop just around the time of one of the biggest demographic changes in UK and US society — World War I. What I don’t know, not being a historian, is just how WWI would affect measles epidemics. Were children mixed more, or less, as their fathers went off to war? Were children taken out of London and other cities, into rural areas, as they were in the second World War? (We know that measles is an urban disease.) And so on. I don’t know enough about population movement and changes in this period to put the story together, but I’m personally convinced that this had a significant effect on measles mortality, and most likely because (somehow) it led to children being infected just a little bit later in their life.

(Edit: In the comments, Tsu Do Nimh [if that’s his real name] points out that 1915 was the time family planning and birth control started. That’s another potential cause of a significant demographic change toward smaller families, which in turn could lead to exposure to measles at a later age.)

I don’t think this is the whole story, but it does seem to be one of the explanations that (in principle) does have enough power to cause a hundred-fold drop in measles case-fatality rates.

• Moving on to the last two categories, which are closely related. It’s well known, now, that vitamin A deficiency greatly increases the risk of death after measles infection. And in England, at the least, in the first third of the 20th century, vitamin A deficiency was common,5 especially in the poor (who were almost entirely at risk of measles-related death; measles was never a big risk to the wealthy).

So vitamin A supplementation presumably must have had a big impact on measles mortality, once it became widespread.

But: First of all, vitamin A supplementation didn’t become part of measles treatment until the early 1930s.6 By that time, the case-fatality rate had already started to drop pretty dramatically, and, as always, we don’t see any sudden drop in the death rate that’s associated with any one factor.

Second, the effect doesn’t seem to be great enough — vitamin A supplementation reduces measles mortality about 2 to 3-fold,7 which is great, but nowhere near enough to account for the hundred-fold reduction in death rates we see.

• Finally: Nutrition. It’s very clear that malnourished measles patients do much, much worse than those who are well nourished. It can be a huge effect, certainly enough to account for the differences in 1910 and 1950 death rates. Patients in the developing world, today, may suffer case-fatality rates that are much more like 1910 London (10-30% death rates) than 1950 and present-day London (0.025% death rates). 8

But my question — and again, I’m no historian — is, how badly malnourished were children in the 1920s? The biggest loss in survival comes from the most malnourished children, from children who are severely malnourished. Just “ordinary” levels of malnourishment “only” cause about a 2- to 5-fold difference in survival.9 Yet again, not enough to account for the 100-fold change in survival by 1950.

Were children in England and the US, in 1920, really comparable to severely malnourished third-world children today? Of course it was almost entirely the poor who died; measles even in the 1910s were known to spare the rich and kill the poor. But even so — Am I naive, or were the ordinary working poor in those days really malnourished to the border of famine?

So there are the general explanations for the increased measles survival from 1915 to 1955. Each of those factors I can easily see causing a 5- or even 10-fold improvement in mortality, but none of them seems, to me, to be enough for the effect we see. There’s some room for synergistic effects, multiplying survival rates rather than additive (better-nourished patients who are less crowded and therefore receive lower doses of virus, getting better treatment after they do get sick) — but equally, there’s a lot of overlap (vitamin A deficiency isn’t completely separate from overall malnourishment).

(This is why I’d really, really like to see if modern measles virus and 1910 measles virus actually were similar at the genome level, or if there might be some change in the virus after all.)

As I said earlier, I’m not an expert on any aspect of this, and I welcome any corrections. (But, again, comments that are your opinion aren’t going to be much help; data and references, please.)

Armstrong, G. (1999). Trends in Infectious Disease Mortality in the United States During the 20th Century JAMA: The Journal of the American Medical Association, 281 (1), 61-66 DOI: 10.1001/jama.281.1.61[↩][↩]

If two “treatments”, A and B, both reduce the fraction of cases that die to 1/3rd the untreated level, then I might expect the combination to reduce death to 1/9th, and call that additive, and only call it synergistic if the effect was even greater (a significant interaction between A and B in statistical jargon). Log(fraction dead) = Ai + Bj + Cij + error, is the model I’m imagining.

I came across several references to oxygen therapy (“Oxygen tents”) in the 1940s literature, but didn’t find a clear reference to when it started.

Doctors in the 1940s clearly considered oxygen treatment to be a major factor, but not the most critical one. From the 1945 round-table discussion I mentioned in Part III:

Improved nutrition was first and foremost, he thought, the cause of the lowered mortality, not the shift in the attack-age, though doubtless it played a part. There was no detectable difference between the character of the measles of 20 years ago and now, but there was a great difference in the nutrition of the children. Moreover, our therapeutic armamentarium was considerably enhanced by the oxygen tent, sulphonamides and penicillin, and by earlier operation for mastoiditis; even suppurative meningitis was not a great menace nowadays, whereas twenty years ago practically every child with meningitis died.

–Butler, W. (1945). The Fatality Rate of Measles: A Study of its Trend in Time. Journal of the Royal Statistical Society 108, 259-285.

(This discussion, as I said, is a completely fascinating one. They didn’t reach a clear conclusion, and the points they raise are more in the thinking-aloud category than definitive solutions; but it’s really intriguing and useful to see the viewpoint at that time.)

How well does the measles decrease coincide with child labor practices? I know that the Fair Labor Standard’s Act wasn’t passed until 1938, but child labor may have been decreasing before then. It may not have been that 1920s children were as malnourished as those in third world countries today, but they would have been crammed together inside poorly ventilated factories.

Another element in the “better treatment” group of factors may be the increasing use (and increasing affordability) of aspirin to reduce fever in the early 20th century. I don’t have handy stats, but I’m fairly sure that there was a direct correlation between duration of high fever in measles cases and subsequent complications, including pneumonia and encephalitis.

Bayer began worldwide distribution of aspirin in 1899, and Bayer’s patents in the US expired in 1917, making generic aspirin widely available.

Of course, there’s a secondary mystery of why Reyes Syndrome was not identified as a side effect of aspirin treatment of viral infections in children until 1963.

chezjake: Interesting thought, but I don’t see a lot of evidence for it. Doctors in the 1910s and 1920s used aspirin for measles, as with other diseases, but didn’t seem particularly impressed by aspirin’s efficacy. I refer you to the rather disparaging comments about aspirin in measles in “Forchheimer’s therapeusis of internal diseases, Volume 2” (Frank Billings, 1919), “An Account of an Epidemic of Measles” (E.W. Gardner, Am J Clin Med 23:925-929 (1916)), and “Infectious Diseases” (Julius L. Salinger, transl. by J.C. Wilson, 1911) among other commentaries of the time.

I think you are “multiple minor changes” territory where each change in demographic, social services, nutrition (when were the pure food laws passed?), and therapy each shoved the mortality down a bit.

I came across several references to oxygen therapy (“Oxygen tents”) in the 1940s literature, but didn't find a clear reference to when it started.

Doctors in the 1940s clearly considered oxygen treatment to be a major factor, but not the most critical one. From the 1945 round-table discussion I mentioned in Part III:

Improved nutrition was first and foremost, he thought, the cause of the lowered mortality, not the shift in the attack-age, though doubtless it played a part. There was no detectable difference between the character of the measles of 20 years ago and now, but there was a great difference in the nutrition of the children. Moreover, our therapeutic armamentarium was considerably enhanced by the oxygen tent, sulphonamides and penicillin, and by earlier operation for mastoiditis; even suppurative meningitis was not a great menace nowadays, whereas twenty years ago practically every child with meningitis died.

–Butler, W. (1945). The Fatality Rate of Measles: A Study of its Trend in Time. Journal of the Royal Statistical Society 108, 259-285.

(This discussion, as I said, is a completely fascinating one. They didn't reach a clear conclusion, and the points they raise are more in the thinking-aloud category than definitive solutions; but it's really intriguing and useful to see the viewpoint at that time.)

I came across several references to oxygen therapy (“Oxygen tents”) in the 1940s literature, but didn't find a clear reference to when it started.

Doctors in the 1940s clearly considered oxygen treatment to be a major factor, but not the most critical one. From the 1945 round-table discussion I mentioned in Part III:

Improved nutrition was first and foremost, he thought, the cause of the lowered mortality, not the shift in the attack-age, though doubtless it played a part. There was no detectable difference between the character of the measles of 20 years ago and now, but there was a great difference in the nutrition of the children. Moreover, our therapeutic armamentarium was considerably enhanced by the oxygen tent, sulphonamides and penicillin, and by earlier operation for mastoiditis; even suppurative meningitis was not a great menace nowadays, whereas twenty years ago practically every child with meningitis died.

–Butler, W. (1945). The Fatality Rate of Measles: A Study of its Trend in Time. Journal of the Royal Statistical Society 108, 259-285.

(This discussion, as I said, is a completely fascinating one. They didn't reach a clear conclusion, and the points they raise are more in the thinking-aloud category than definitive solutions; but it's really intriguing and useful to see the viewpoint at that time.)

Enjoyed these articles a lot. I wonder if a drop in bacterial carriage over the period might also be a major factor. Don’t know if anyone has any evidence for such a reduction but improvements in hygiene and a reduction in crowding are likely to reduce carriage rates and therefore the risk of co-infection.

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